Acquired C1 esterase inhibitor deficiency in lymphomas: prevalence, symptoms, and response to treatment.

We retrospectively studied the prevalence of C1 esterase inhibitor (C1 INH) deficiency in 131 patients with various lymphomas. We determined C1 INH activity, C1 INH antigen, and C4 concentration at diagnosis and after chemotherapy. In follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL) and chronic lymphocytic leukemia (CLL) consecutive patients were studied. In these entities, the prevalence of C1 INH deficiency was 10.2% in DLBCL, 4.1% in CLL, and 0% in FL and Hodgkin lymphoma. In indolent lymphomas, we identified only single cases of C1 INH deficiency, predominantly in splenic marginal zone lymphomas (SMZL) (four cases). Only three patients were symptomatic while the majority (11 cases) was asymptomatic. In DLBCL patients who were successfully treated with chemotherapy, complete normalization of C1 INH activity and C4 was observed. In contrast, C1 INH deficiency remained in SMZL patients after splenectomy. We conclude that C1 INH deficiency in lymphomas is frequently asymptomatic and responsive to immunochemotherapy.

Probability of remaining in unsustained complete remission after steroid therapy withdrawal in patients with primary warm-antibody reactive autoimmune hemolytic anemia.

BACKGROUND: Primary warm autoimmune hemolytic anemia (WAIHA) is a rare autoimmune disorder frequently responding to corticosteroid first-line treatment and effective second-line treatment options such as splenectomy or anti-CD20 antibody therapy. Disease management is frequently hampered by a lack of evidence. METHODS: We have investigated the probability of sustained treatment-free remission after steroid induction to facilitate clinical decision making regarding timing and necessity of second-line treatments. Response data from 31 patients with primary WAIHA initially treated with steroids were retrospectively analyzed. All patients responded by achieving a hemoglobin of at least 10 mg/dl. RESULTS: After steroid tapering and final withdrawal, 9 of 30 patients remained in unsustained complete remission (CR). The probability of remaining in CR after steroid treatment only was 38.2 % (2 SD 20.6 %) at 15 months. The median remission duration was 100 + months with a range of 12 + to 163 + months. Of note, none of the remaining patients still on steroids achieved CR beyond 15 + months. CONCLUSION: These data indicate that a considerable proportion of patients do not need further treatment and that relapses will not occur after 15 months in CR.

Interleukin-10 inhibits autonomous myelopoiesis in patients with myelofibrosis.

The spontaneous formation of colony-forming units granulocyte/macrophage (CFU-GM) in semisolid cultures has been shown to be due to the endogenous release of cytokines and/or to the hypersensitivity of cells against growth factors. We have reported that increased autonomous CFU-GM growth is an in vitro characteristic of myelofibrosis (MF) which may reflect aberrant hematopoiesis in vivo. Because of its cytokine synthesis-inhibiting action, we speculated that interleukin-10 (IL-10) may inhibit pathological overproduction of myeloid cells in MF by suppression of autonomous myelopoiesis. In this study, IL-10 significantly inhibited autonomous CFU-GM formation in vitro from peripheral blood mononuclear cells (PB MNC) in 10 of 11 patients with MF tested. In all patients, there was a mean inhibition of 69% ranging from 35% to 100%. Suppression of autonomous CFU-GM formation by IL-10 was dose dependent and reversible by the addition of anti-IL-10 antibodies. Our results indicate that IL-10 is a potentially useful molecule to affect aberrant myelopoiesis in patients with MF.

Cold antibody autoimmune hemolytic anemia and lymphoproliferative disorders: a retrospective study of 20 patients including clinical, hematological, and molecular findings.

A total of 20 patients with cold antibody hemolytic anemia were evaluated in a retrospective study of them, 15 had a monoclonal gammopathy of unknown significance (MGUS): 14 with MGUS of immunoglobulin M (IgM) subtype and 1 with immunoglobulin G subtype. One patient had smoldering Waldenström's macroglobulinemia, but four patients had no monoclonal protein and no evidence of lymphoma. However, in three of these patients, we were able to demonstrate a (mono-)clonal rearrangement of their immunoglobulin heavy and/or light chains. Of the 20 patients, 5 had IgHV34 nucleotide sequence indicating that the antibody was directed against the "I" antigen. Two patients exhibited a progressive increase of IgM over time, however without increasing hemolytic activity. Moreover, in two patients with long-term follow-up, we were able to correlate recurrent hemolytic activity with low environmental temperatures. Among four patients treated with rituximab, all four responded to treatment. However, treatment effect was only transient in all of them.

Explaining survival differences between two consecutive studies with allogeneic stem cell transplantation in patients with chronic myeloid leukemia.

PURPOSE: In the two consecutive German studies III and IIIA on chronic myeloid leukemia, between 1995 and 2004, 781 patients were randomized to receive either allogeneic hematopoietic stem cell transplantation with a related donor or continued drug treatment. Despite comparable transplantation protocols and most centers participating in both studies, the post-transplant survival probabilities for patients transplanted in first chronic phase were significantly higher in study IIIA (144 patients) than in study III (113 patients). Prior to the decision on a combined analysis of both studies, reasons for this discrepancy had to be investigated. METHODS: The Cox proportional hazard cure model was used to identify prognostic factors for post-transplant survival. RESULTS: Donor-recipient matching for human leukocyte antigen, patient age, time between diagnosis and transplantation, and calendar time showed a significant influence on survival and/or the incidence of cure. Added as a further factor, affiliation to study IIIA had no significant impact any longer. CONCLUSIONS: Discrepancies in influential prognostic factors explained the different post-transplant survival probabilities between the studies. The significance of calendar time suggests a lack of consistency of transplantation practice over time. Accordingly, the prerequisite for a common assessment of overall survival in the two randomized transplantation arms was not met. Moreover, our analyses provide an independent validation of established prognostic factors and their cutoffs. The statistical approach in investigating and modeling potential prognostic factors for survival sets an example for the examination of studies with unexpected outcome differences in concurrent treatment arms.

Immune-mediated disorders causing bleeding or thrombosis in lymphoproliferative diseases.

Bleeding and thrombosis are important complications in patients with malignant lymphomas. They may be due to direct actions of the lymphoma, such as venous compression or bone marrow infiltration, but they may also be caused by paraneoplastic phenomena, which are immune-mediated in most of the cases. The most important paraneoplastic immune-mediated disorders in lymphomas causing bleeding are autoimmune thrombocytopenia, acquired hemophilia A and acquired von Willebrand syndrome. In addition, there are a variety of other less common immune-mediated bleeding conditions, such as acquired thrombasthenia, acquired factor X-, V-, XI-, XII-, or prothrombin deficiency. The presence of antiphospholipid antibodies is a rare condition predisposing to venous and arterial thrombosis and there are other very uncommon conditions, which predispose exclusively to arterial thrombosis such as hyperlipidemic xanthomatosis. Interestingly, there is hardly any correlation between the histological type and the aggressiveness of lymphoma and the type and prevalence of the immune-mediated conditions. Successful treatment of the underlying lymphoma is often associated with definite and sustained resolution of the immune-mediated disorder.

Cancer-related microangiopathic hemolytic anemia: clinical and laboratory features in 168 reported cases.

Cancer-related microangiopathic hemolytic anemia (CR-MAHA) is a paraneoplastic syndrome characterized by Coombs-negative hemolytic anemia with schistocytes and thrombocytopenia. We reviewed and analyzed all cases of CR-MAHA reported since 1979 (the time of the last published review on this topic) according to predefined criteria. We found 154 cases associated with solid cancer and 14 with lymphoma. Among the solid cancers, gastric, breast, prostate, lung, and cancer of unknown primary (CUP) were most common; 91.8% of cancers were metastatic, and in 19.4% of solid cancers CR-MAHA did not occur until recurrence of cancer. Lymphoma cases included Hodgkin disease, angiotropic lymphoma, diffuse large cell lymphoma, and myeloma. Evaluation of the clinical and laboratory findings revealed that only a minority of cases presented with the features of thrombotic thrombocytopenic purpura (TTP) or atypical hemolytic uremic syndrome (aHUS), with the exception of prostate cancer, where aHUS was a common presentation. Compared to hereditary or immune TTP or aHUS, disseminated intravascular coagulation and pulmonary symptoms were more common in CR-MAHA. Plasma exchange or fresh frozen plasma was rarely effective except in prostate cancer patients with aHUS. CR-MAHA responded to antitumor therapy in many patients with gastric, breast, lung, and CUP cancers. These patients had a superior survival compared to patients without chemotherapy. Compared to the prognosis of patients with metastatic cancer without CR-MAHA, the prognosis of CR-MAHA patients was greatly inferior. There is evidence that some cases of CR-MAHA in lymphoma are immune mediated.

Inhibitor development in two patients with mild haemophilia A - spontaneous disappearance and no recurrence of the inhibitor after re-challenge.

Inhibitors against factor VIII (FVIII) complicate the treatment of patients with haemophilia. In mild haemophilia, the development of antibodies against FVIII is rare. However, the occurrence of an inhibitor in mild haemophilia changes the bleeding phenotype from mild to severe, and thus becomes a major clinical problem. We report on two patients with mild haemophilia A (FVIII level 8 and 27%, respectively), who have a missense mutation in exon 16 (G to A transition in codon 1773) and exon 22 (T to C transition in codon 2096), respectively. Both mutations have not been described in the Haemophilia A Mutation, Structure Test and Resource Site. Our patients developed high titer inhibitors following an intensive FVIII replacement therapy due to a muscle bleeding and after a polytrauma. During the presence of the inhibitor, AICC or FVIIa was successfully used as bypassing agent. In both patients the inhibitor disappeared spontaneously. Years after the development of the inhibitor, the patients again received FVIII concentrates. Reappearance of the inhibitor was not observed in either patient. The reported cases indicate that inhibitors in patients with mild haemophilia might be transient and disappear spontaneously. Therefore, the necessity of immune tolerance therapy, which is costly and strenuous for the patients, should be critically examined for each individual patient and a watch and wait strategy might be advisable.

Paraneoplastic autoimmune thrombocytopenia in solid tumors.

Immune-mediated hematological diseases are rare, but typical paraneoplastic syndromes. We have critically analyzed 68 published cases of an association of autoimmune thrombocytopenia (ITP) and solid cancers. Such cases occurred in a variety of cancers. They were most common in patients with lung and breast cancer, very rare in prostate cancer, but relatively common in renal cell and ovarian cancers. ITP occurred in about half of the patients concurrently with cancer, in about 25% prior to cancer and in others some time after diagnosis and treatment of cancer. In the latter patients ITP was either a sign of recurrence of cancer or had other causes. In most patients ITP responded to steroid treatment. There were only few patients who had a complete response of ITP after surgical removal or chemotherapy of the cancer and there was only one patient (ITP prior to cancer) in whom a long lasting complete remission of ITP after cancer resection could be ascribed solely to cancer resection. We believe that in patients with ITP a cancer-associated ITP has always to be considered, but an extensive search for a present or future cancer is not indicated unless there is laboratory or clinical suspicion of a malignant disease. In patients with cancer associated ITP cancer resection should be done in non-metastatic cases (after appropriate pretreatment). In metastatic cases steroids are probably the treatment of choice.

Acquired immune-mediated thrombophilia in lymphoproliferative disorders.

We analyzed 66 cases of immune-mediated thrombophilia in patients with lymphoma reported in the literature. Sixty-one cases had a lupus anticoagulant, three an antibody to protein S, one to protein C, and one to ADAMTS 13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13). Lupus anticoagulants occurred in all histological subtypes of non-Hodgkin lymphoma, except mantle cell lymphoma, MALT (mucosa-associated lymphoid tissue) lymphoma, and angioimmunoblastic T-cell lymphoma, and rarely in Hodgkin lymphoma. The largest number of cases was described in splenic marginal zone and lymphoplasmacytic lymphoma. Lupus anticoagulants were highly associated with immunoglobulin M (IgM) paraproteinemia, autoimmune hemolytic anemia, and immune thrombocytopenia. About half of the patients had thrombotic events (antiphospholipid antibody syndrome). Venous thromboembolism was more than twice as common as arterial thrombosis; 6.5% had a catastrophic antiphospholipid antibody syndrome. The lupus anticoagulant could be eliminated by lymphoma treatment (chemoimmunotherapy or splenectomy) in more than one-third of patients. It is suggested that a search for lupus anticoagulant should be done in all patients with lymphoma, because a diagnosis of lupus anticoagulant may influence the management of lymphomas in some patients.

Improved outcome in patients with chronic myelogenous leukemia after allogeneic hematopoietic stem cell transplantation over the past 25 years: a single-center experience.

Although imatinib has become standard first-line therapy in chronic myelogenous leukemia (CML), allogeneic hematopoietic stem cell transplantation (HSCT) is still considered to be an important treatment alternative for patients with drug resistance or advanced disease. We retrospectively analyzed 175 adult CML patients who underwent HSCT at our institution between 1983 and 2007, with the aim to compare outcomes in patient subgroups and to identify prognostic variables. The median follow-up was 65 months. The probability of overall survival (OS) for all patients was 62%, with a significant improvement seen in the imatinib-era (2001-2007) compared to previous time periods (P <.05). Furthermore, a significantly better outcome for patients with chronic phase CML compared to patients with accelerated or blast phase could be observed (P < .05). Cumulative incidence (CI) of treatment-related mortality (TRM) was 9.7% at 100 days and 1 year after HSCT. CI of relapse was 5% at 1 year and 7.5% at 3 years after HSCT. Post-HSCT outcome was not influenced by pretreatment therapy with imatinib, donor type, or a conditioning regimen with total body irradiation (TBI). These data confirm earlier observations and suggest that allogeneic HSCT is still an important treatment option for high-risk patients with CML, and should thus remain an integral component in current and future treatment algorithms.

How I treat autoimmune hemolytic anemias in adults.

Autoimmune hemolytic anemia is a heterogeneous disease with respect to the type of the antibody involved and the absence or presence of an underlying condition. Treatment decisions should be based on careful diagnostic evaluation. Primary warm antibody autoimmune hemolytic anemias respond well to steroids, but most patients remain steroid-dependent, and many require second-line treatment. Currently, splenectomy can be regarded as the most effective and best-evaluated second-line therapy, but there are still only limited data on long-term efficacy and adverse effects. The monoclonal anti-CD20 antibody rituximab is another second-line therapy with documented short-term efficacy, but there is limited information on long-term efficacy and side effects. The efficacy of immunosuppressants is poorly evaluated. Primary cold antibody autoimmune hemolytic anemias respond well to rituximab but are resistant to steroids and splenectomy. The most common causes of secondary autoimmune hemolytic anemias are malignancies, immune diseases, or drugs. They may be treated in a way similar to primary autoimmune hemolytic anemias, by immunosuppressants or by treatment of the underlying disease.

Autoimmune hemolytic anemia as a paraneoplastic phenomenon in solid tumors: A critical analysis of 52 cases reported in the literature.

Autoimmune hemolytic anemia (AIHA) is a well known paraneoplastic phenomenon in lymphoproliferative disorders but there are also a number of case reports of such an association with solid tumors. We have analysed 52 cases of this association reported in the literature. We found that AIHA may occur prior to, concurrent with cancer or well after end of treatment, either as a sign of recurrence or in complete remission of the cancer. 70% of the patients had warm antibody and 30% cold antibody AIHA. Some patients had additional antibodies such as platelet antibodies (Evans syndrome), lupus anticoagulants or antibodies to C1 esterase inhibitor. AIHA occurred in almost all types of cancers, but it was relatively more common in renal cell cancer and Kaposi sarcoma compared to other cancers. In early stage cancers, in particular in renal cell cancers, curative resection of the cancers led to complete, often sustained remission of AIHA within a short time in a number of patients. Resection of the tumor had also beneficial effects in some metastatic cancers. Patients who had a response to resection of the tumor were often refractory to steroid treatment before surgery, while some responses to steroids were observed in patients with metastatic cancer. The study of cancer patients with autoimmune diseases may provide important insights into the biology of tumors.

Paraneoplastic autoimmune cytopenias in Hodgkin lymphoma.

Autoimmune cytopenias are typical paraneoplastic phenomena in malignant lymphomas. We assessed the occurrence, clinical, and laboratory features as well as the response to treatment of autoimmune hemolytic anemia, autoimmune thrombocytopenia, and neutropenia in published cases of Hodgkin lymphomas (HL). We identified 34 cases of an association between HL and autoimmune hemolytic anemia and 48 cases of an association of autoimmune thrombocytopenia (AITP) and HL. The autoimmune cytopenias (AIC) may occur prior to, concurrent with, at the time of recurrence of lymphoma or in complete remission after treatment. Almost all autoimmune hemolytic anemias were caused by warm antibodies. Patients with HL with AIC are more commonly males and are more likely to have mixed cellularity (MC) HL. HL is the only lymphoma which may be associated with autoimmune neutropenia. In contrast to AIC in diffuse large B-cell lymphoma (DLBCL), early stage is less common in patients with HL with AIC. AIC in HL respond better to antilymphoma treatment than to steroids, with the exception of post-treatment AITP in CR of HL which responds easily and durably to steroids.

Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group.

Diagnosis and management of immune thrombocytopenic purpura (ITP) remain largely dependent on clinical expertise and observations more than on evidence derived from clinical trials of high scientific quality. One major obstacle to the implementation of such studies and in producing reliable meta-analyses of existing data is a lack of consensus on standardized critical definitions, outcome criteria, and terminology. Moreover, the demand for comparative clinical trials has dramatically increased since the introduction of new classes of therapeutic agents, such as thrombopoietin receptor agonists, and innovative treatment modalities, such as anti-CD 20 antibodies. To overcome the present heterogeneity, an International Working Group of recognized expert clinicians convened a 2-day structured meeting (the Vicenza Consensus Conference) to define standard terminology and definitions for primary ITP and its different phases and criteria for the grading of severity, and clinically meaningful outcomes and response. These consensus criteria and definitions could be used by investigational clinical trials or cohort studies. Adoption of these recommendations would serve to improve communication among investigators, to enhance comparability among clinical trials, to facilitate meta-analyses and development of therapeutic guidelines, and to provide a standardized framework for regulatory agencies.

The postoperative splenic/portal vein thrombosis after splenectomy and its prevention--an unresolved issue.

Patients undergoing splenectomy have an increased risk of splenic/portal vein thrombosis. We used several databases to identify publications dealing with this risk and analyzed incidence, risk factors and outcome. The risk of splenic portal vein thrombosis has been addressed in prospective and retrospective randomized or non-randomized studies. All studies combined, the overall risk is 3.3%. Risk factors are big spleens (i.e. myeloproliferative disorders) and hereditary hemolytic anemias, whereas the risk is low in autoimmune thrombocytopenia and trauma. The incidence is approximately the same in laparoscopic and open splenectomy. The median time from splenectomy to symptomatic splenic vein thrombosis is 8-12 days. Postoperative antithrombotic prophylaxis ranged from no prophylaxis to heparin for seven days or longer. Treatment of symptomatic splenic vein thrombosis with heparin and warfarin leads to complete resolution of thrombosis in 67%, to partial resolution in 13%, but persistent occlusion, portal hypertension or cavernoma occurred in 20%.The long-term outcome of treatment failures is unknown. Well-designed randomized studies on the prophylaxis of venous thromboembolism after splenectomy are urgently needed.

Diagnosis and treatment of autoimmune haemolytic anaemias in adults: a clinical review.

Autoimmune haemolytic anaemia (AIHA) is an immune disorder caused by antibodies directed against unmodified autologous red cells. The disorder may be a primary (idiopathic) or a secondary disease. The diagnosis is based on the presence of anaemia, signs of haemolysis with reticulocytosis, low haptoglobin, increased lactate dehydrogenase, elevated indirect bilirubin, and a positive direct antiglobulin test (Coombs test). Sometimes, not all of these typical features are present. Most AIHA are caused by warm antibodies, whereas cold antibodies are less commonly detected. While half of the warm antibody-based AIHA are idiopathic anaemias, almost all cold antibody AIHA are secondary anaemias. Underlying diseases are Non Hodgkin's lymphomas and systemic autoimmune disorders, and less frequently organ transplantation, infections, or solid tumors. Moreover, AIHA is an important complication of treatment with nucleoside analogs. Most patients with AIHA require therapy. In warm antibody AIHA, standard first line therapy are glucocorticosteroids with or without high dose immunoglobulins, whereas splenectomy is considered second-line therapy. Response rates of primary AIHA to corticosteroid therapy are high. After initial remission, the dose should be tapered down slowly and with caution, and in some cases, low-dose maintenance therapy is required. The efficacy of standard therapy is low in secondary AIHA that develops in lymphoma patients, posttransplant patients, or tumor patients. Among other immunosuppressive treatments, rituximab (anti-CD20) appears to be highly effective in patients with warm antibody AIHA refractory to standard therapy. Mycophenolate mofetil is quite effective in AIHA patients with an underlying autoimmune or lymphoproliferative disease. Patients with cold agglutinins are refractory to steroids and splenectomy. Half of these patients may respond to rituximab, although responses usually are short-lived. Sometimes, AIHA that is associated with malignant lymphomas or tumors, disappears after successful anti-lymphoma or anti-tumor therapy.

Autoimmune thrombocytopenia in non-Hodgkin's lymphomas.

Autoimmune thrombocytopenia is a common immunehematologic complication in non-Hodgkin's lymphomas and may complicate the treatment. We analyzed an original series from our institute as well as published cases of non-Hodgkin's lymphomas (excluding chronic lymphocytic leukemia) associated with autoimmune thrombocytopenia with regard to demographic factors, prevalence in non-Hodgkin's lymphoma subtypes and treatment outcome. The male/female ratio is 1.75. Half of the cases occurred prior to diagnosis of lymphoma. Chemotherapy is the best treatment in many non-Hodgkin's lymphomas patients with autoimmune thrombocytopenia compared with standard treatment of autoimmune thrombocytopenia. Splenectomy is effective in splenic marginal zone lymphoma. Autoimmune thrombocytopenia in patients with non-Hodgkin's lymphomas is potentially life-threatening and difficult to treat.

Risk of recurrence after a first venous thromboembolic event in young women.

BACKGROUND AND OBJECTIVES: Few data are available on the long-term risk of recurrence of venous thromboembolism (VTE) and on the impact of established thrombosis risk factors in young women. We aimed to study the recurrence rate and the predictive value of laboratory and clinical thrombosis risk factors in young women. DESIGN AND METHODS: Three-hundred and sixty-one women with a first objectively confirmed VTE under 45 years of age (median age 29.6 years, interquartile range 21.9-36.9) known to our outpatient department were included in this retrospective analysis. These women were re-examined with regard to recurrence of thrombosis and laboratory thrombosis risk factors. RESULTS: Within a median observation period of 11.3 years, recurrent VTE occurred in 141 patients (39.2%). The cumulative probability of recurrence was 10.9% after 2 years, 29% after 10 years and 56% after 20 years. There were no significant associations between recurrence of VTE and laboratory risk factors such as natural inhibitor deficiency, factor V Leiden, the G20210A prothrombin variation, elevated factor VIII or hyperhomocysteinemia. Even women with more than one risk factor were not found to have a higher risk of recurrent VTE. Among the clinical characteristics only an increased body mass index (p=0.03) was associated with a higher probability of recurrence. INTERPRETATION AND CONCLUSIONS: The risk of recurrent VTE in young women is higher than previously expected and remains constant over at least 20 years. Neither clinical features nor laboratory parameters help predict this risk. Thus, also in young women VTE should be regarded as a chronic disease.

Autoimmune hemolytic anemias, Evans' syndromes, and pure red cell aplasia in non-Hodgkin lymphomas.

We analyzed 108 cases of non-CLL non-Hodgkin lymphoma (NHL) associated with autoimmune hemolytic anemia (AIHA) (+/- pure red cell aplasia (PRCA)) or Evans' syndrome. The analysis was based on cases reported in the literature, which were retrieved by means of Pubmed and Medline searches and of an original series of 121 patients with NHL as well as reference lists of papers in the field. The number of cases in various NHL subtypes was small (n = 6-25). Nevertheless, interesting and sometimes unexpected differences in sex prevalence, temporal relationship between onset of lymphoma and AIHA, stage of lymphoma, relative frequency of warm antibody-AIHA (WA-AIHA) and cold antibody (CA-AIHA), association with PRCA and response of AIHA to treatments were noted for various lymphoma entities. WA-AIHA was more frequent in B-cell lymphomas, while CA-AIHA and PRCA predominantly occurred in T-cell lymphomas. Anti-lymphoma treatment seemed to be more effective against AIHA than conventional therapy with steroids or immunoglobulin. Although generated by a literature survey, this compilation of data indicates a complex relation of lymphoma and AIHA and warrants more attention and specific studies.